This invention relates generally to transdermal and transmucosal drug delivery (TDD) devices. More particularly, the invention relates to TDD devices for delivering heat sensitive or volatile drugs in which the drug is extruded as a gel onto an adhesive layer following which the surface of the adhesive layer onto which the gel has been extruded is laminated with a second adhesive layer to form a drug-containing adhesive composite device. Chemical enhancers for facilitating transport of the drug through the skin or mucosa and other additives can also be mixed with the drug or into the composite. Thus, the invention encompasses a method for making TDD devices using an extrusion step to incorporate a gelled drug into a dried adhesive layer, and to drug delivery devices made using the method. These methods and devices are particularly useful for delivering nicotine into the body.
Cigarette smoking is a major risk factor in coronary heart disease and is the cause of approximately 30% of all cancer deaths. However, smoking is difficult to give up, and any smoking cessation therapy has to deal with both the pharmacological and psychological dependence on cigarettes. Modest success has been obtained by separating the treatment of these two factors, such as by satisfying the pharmacological craving with nicotine pills or chewing gum while treating the psychological addiction independently.
One of the most successful approaches relies on nicotine chewing gum, which achieves direct delivery of nicotine to the systemic circulation by buccal absorption. However, nicotine chewing gum tastes bad, may lead to mouth ulcers and heartburn, and destroys dental appliances. Further, patient compliance is crucial to effectiveness. Other problems with orally administered nicotine include stomach upsets, nausea, rapid nicotine degradation, and irregular and unpredictable blood levels.
Another approach gaining increasing favor for treating the pharmacological dependence on cigarette smoking is transdermal delivery of nicotine. The skin is ordinarily a very effective barrier to passage of materials from the environment into the body. However, nicotine is very volatile, highly lipid soluble, and permeates the skin easily. For example, a comparison of average penetration rates of other transdermally administered agents through the skin show that nitroglycerin has a skin flux of 10-25 .mu.g/cm.sup.2.h, scopolamine 2-8 .mu.g/cm.sup.2.h, estradiol 0.01-0.03 .mu.g/cm.sup.2.h, clonidine 0.5 .mu.g/cm.sup.2.h, and nicotine 100-300 .mu.g/cm.sup.2.h. However, nicotine is also very irritating to skin and is very toxic. Therefore, development of acceptable TDD devices for delivering nicotine has required finding ways to minimize the irritation and safety problems while supplying effective doses of the substance.
A number of TDD devices for delivering nicotine have been described. Japanese Laid Open Application No. 61-251619 reports a non-controlled release device that holds low amounts of the substance and covers a relatively large area (70 cm.sup.2) of skin. U.S. Pat. No. 4,597,961 to Etscorn discloses a device in which a microporous membrane minimally controls release of nicotine to the skin such that it is effective for only about 45 minutes. U.S. Pat. Nos. 4,920,989 and 5,016,652 to Rose et al. describe a nicotine patch that is preferably used with a nicotine aerosol spray that is delivered into a patient's mouth. U.S. Pat. No. 4,943,435 to Baker et al. reports a transdermal patch for delivering nicotine for periods of 12-24 hours that includes a nicotine reservoir and rate-controlling polymer matrix to regulate nicotine diffusion through the skin. U.S. Pat. No. 4,908,213 to Govil et al. discloses a transdermal nicotine patch containing an antipruritic to counteract severe itching that may occur with transdermal administration of nicotine. U.S. Patent No. 4,877,618 to Reed teaches a transdermal nicotine patch containing a stack of alternating adhesive and interlaminar layers for providing a relatively constant rate of diffusion through the skin over an extended period of time.
Methods of fabricating TDD devices have not received much attention in the patent literature. U.S. Pat. No. 4,943,435 to Baker et al. discloses a method of making a nicotine patch wherein the nicotine is preferably dissolved in an inert polymer matrix that controls the rate of nicotine release. The percentage by weight of nicotine can be varied according to the desired loading in the monolithic matrix layer, however, above about 50% nicotine by weight the polymer fails to solidify properly after casting, remaining in a gel or fluid form. Thus, this method of making nicotine patches is limited to polymers and nicotine loads that, when mixed, polymerize properly.
Another problem of drug delivery devices containing polymers and volatile drugs is that, even if polymerization is achieved in the presence of the drug, the polymer-drug combination must be allowed to dry. This is a problem for volatile drugs, such as nicotine, since the concentration of the volatile drug will diminish during drying, especially if the polymer is heated in an oven to accelerate drying. Thus, it would be advantageous to avoid fabrication methods requiring heating or drying after addition of a volatile drug to the polymer.
Baker also teaches that many of the common materials from which components of TDD devices, such as backings, adhesives, membranes, matrices, and release liners, are dissolved or degraded by nicotine. For example, Baker teaches that adhesives become stringy, lose their tackiness, or become so heavily loaded with nicotine that they deliver a huge burst of nicotine when applied to the skin. According to Baker, typical grades of polyisobutylene, acrylate, or silicone-based adhesives behave this way when exposed to nicotine for periods as little as one week. Baker further teaches that polymers that swell significantly, disintegrate, or dissolve completely in the presence of nicotine include many grades of polyvinyl chloride, polycarbonate, polystyrene, polyethylene terephthalate, polybutyrate, polyurethane, ethylene-vinyl acetate copolymers (except those with low percentages of vinyl acetate), and polyvinylidene chloride.
U.S. Pat. No. 4,915,950 to Miranda et al. describes a method for making TDD devices that involves laminating an anchor adhesive layer onto a drug-impermeable backing. Similarly, a pressure-sensitive contact adhesive is laminated onto a release liner. Then, an adsorbent source layer is deposited onto, preferably, the contact adhesive, or the anchor adhesive. A drug in liquid form is then printed onto the exposed face of the adsorbent source layer. Finally, the anchor adhesive/backing laminate is laminated onto the source/contact adhesive/release liner laminate to form the finished device. The printing step involves depositing the liquid drug onto the adsorbent source layer in a substantially uniform manner by any of a number of techniques. Use of a drug in a liquid form is a substantial problem because the drug must wet the surface of the source layer so that squeezing of liquid to the periphery of the device during lamination is substantially prevented. After deposition, the drug diffuses into one or both of the adjacent adhesive layers. Thus, the fabric material composing the source layer and its surface properties must be carefully selected so that wicking into the fabric is carefully controlled. The rate at which the liquid drug is printed onto the source layer and the subsequent lamination to the adhesive laminate,therefore, must be carefully controlled as well, which is difficult to do.
U.S. Pat. No. 5,110,599 to Anhauser also discloses a method for producing transdermal patches through a printing process.